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Dec. 1933 A M E R I C A N P H A R M A C E U T I C A L A SS OC IA TIO N 1241
Q U A L I T A T I V E TESTS F O R E P H E D R I N E A N D ITS DERIVATIVES*,
BY
C.
T.
FENG AND B. E.
READ.
In the course of our research upon the best quantitative method of assay for
ephedra and its alkaloids we undertook a large number of qualitative tests with a
view of possibly finding one which would prove of worth in quantitative work.
While this has not been definitely attained much useful information has been
brought together concerning the reaction of ephedrine and its derivatives toward
various laboratory reagents which we herewith report.
Chen in 1925 (1) in one of his first reports from these laboratories gave a list of
reactions of ephedrine with several of the commoner laboratory reagents, and later
Chen and Kao (1926) (2) summarized the various tests known q. v., which it is
unnecessary for
us
to go over again now.
Tsiang and Brown (1927) (7) gave a more complete report upon the gold and
platinum salts made with solutions of ephedrine varying in strength from 1 n 10,000
to
1
in 1000. With Krant s reagent they obtained a characteristic crystalline
precipitate.
On account of the fact th at Chinese ephedra has been shown to contain a)
ephedrine, b ) pseudoephedrine (6), and (c) methyl-ephedrine 5), we have care-
fully extended our tests to all three of these compounds; also to the
d)
butyl,
e )
benzyl and f) quaternary halide compounds which have been synthesized in
these laboratories 4).
Unless indicated otherwise, solutions of the above compounds were found to
give their best reactions in the following concentrations:
a )
and b ) five to ten per
cent,
(c)
two and a half to five per cent, d ) and e ) one to two and a half per cent,
and
(f)
one-tenth to one per cent.
1. BIURET TEST MODIFIED) 3).
(a)
b )
(c)
Ephedrine Hydrochloride.-A violet pigment very soluble in ether giving a brilliant
solution, which when evaporated to dryness yields
a
gelatinous residue (3).
Pseudoephedrine Hydrochloride.-The pigment is more slowly soluble in ether yielding
a solution of dull appearance, which when air dried produces beautiful violet crystals (3).
Methyl-Ephedrine Hydrochloride.-Vigorous shaking of the reaction mixture showed
th at the pigment was not ex tractable by ether, bu t before shaking the ether dissolved some of
the pigment.
(d) Butyl-Ephedrine Hydrochloride.-Identical with c ) .
(e)
f)
Benzyl-Ephedrine Hydrochloride.-The pigment was absolutely insoluble and was not
Quaternary Halide.-No biuret coloration produced.
extractable by ether.
2
POTASSIUM IODIDE TEST. A SATURATED SOLUTION ADDED TO A FIVE PER CENT
SOLUTION OF EACH COMPOUND.
(a) Prisms or rhombic bars. (Fig.
1.
b ) Hexagonal rhomboid plates. (Fig. 2.)
(c) Slowly producing thin flaky crystals. (Fig.
3.)
d )
Producing oily drops immediately, from which rosettes separate later. (Fig. 4.
The cost of these experiments was defrayed par tly by a grant from the Council on
From the Depar tment of Pharmacology, Peiping Union Medical College, Peiping, China.
Pharmacy and Chemistry of th e American Medical Association.
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1242
JOURNAL
OF
THE Vol.
X X I I ,
No. 12
Fig. 10. Fig. 11. Fig. 12.
Fig. 1.-Potassium iodide and ephedrine hydrochloride. Fig. 2.-Potassium iodide and
Fig. 3.-Potassium iodide and methyl-ephedrine hydrochloride.
Fig. 4.-Potassium iodide and butyl-ephedrine hydrochloride. Fig. 5.-Cadmium potas-
Fig. 7.-Picric acid an d ephedrine.
Fig. 9.-
Fig. 10.-Ammonium thiocyanate and ephedrine. Fig. 11.--Ammonium thiocyanate and
pseudoephedrine hydrochloride.
sium iodide and ephedrine.
Picric acid and methyl ephedrine.
pseudoephedrine.
Fig. 6.-Cadmium potassium iodide and methyl ephedrine.
Fig. 8.-Picric acid an d pseudoephedrine.
Fig. 12.-Ammonium thiocyanate and methyl ephedrine.
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Dec.
1933
AMERICAN PHARMACEUTICAL ASSOCIATION
1243
e ) Oily droplets which do not crystallize in one or two hours.
f) Readily producing clusters of characteristic rhombic crystals 4).
3.
AURIC CHLORIDE. THREE PER CENT, MICRO-TEST
(7).
a )
6)
(c)
d )
e ) Similar to d) .
(f)
Characteristic crystals.
The butyl-ephedrine mixture d ) evaporated to dryness yields a gelatinous mass which in
Golden-yellow sharp needles, soluble in water and alcohol.
Golden-yellow feathery needles, soluble in water and alcohol.
Yellow prisms, soluble in water and alcohol.
Yellow oily drops, slightly soluble in water, readily in alcohol.
scveral days crystallizes out , benzyl-ephedrine yields no crystals.
4.
PLATINIC CHLORIDE. TWO PER CENT, MICRO-TEST
(7).
a )
b )
c)
d )
in alcohol.
e )
1)
Pale yellow silky needles, very soluble in water or alcohol.
Pale yellow bunches of long needles, very soluble in water or alcohol.
Characteristic yellow needles, soluble in water or alcohol.
Pale yellow rhombic-hemihedral crystals. Slightly soluble in water an d very soluble
A quicker reaction than t ha t with auric chloride.
Pale yellow drops.
Characteristic fine needles (already published, Feng 1932 4)).
Slightly soluble in water, very soluble in alcohol.
5.
CADMIUM POTASSIUM IODIDE. TWENTY PER CENT.
a) Oily droplets separate which on standing crystallize out. (Fig.
5 . )
Readily soluble
b ) Similar to
a ) .
c) On standing clusters of characteristic needles are formed. Soluble in water. (Fig. 6.)
d )
Slightly
soIuble
in
water.
e ) Similar to d ) .
c f
All of the above crystalline precipitate s are soluble in alcohol or acetic acid.
in water.
Oily.droplets first appear, which later crystallize out in irregular forms.
Fine flakes readily separate out which are almost insoluble in water.
6.
PICRIC
ACID.
ONE
PER
CENT,
MICROCHEMICAL TEST.
e)
(Fig.
7 . )
6 )
thorns. (Fig. 8.)
(c)
Yellow feathery leaflets, soluble in water. (Fig. 9.)
d )
e )
c f
These results are sufficiently characteristic to be used
to
distinguish these six compounds
one from the other. It is important to use the strengths of solutions given at the beginning
of
this report, earlier workers using weaker solutions reported negative results (I); ephedrine in
strong solution certainly yields a crystalline precipitate with picric acid one per cent.
Yellow needle-shaped crystals, readily soluble in water.
Yellow needle-shaped crystals, soluble in water.
Shaped like pine needles.
Less fine than
a),
haped like
Yellowish flakes, slightly soluble in water.
Yellowish globules, slightly soluble in water.
Characteristic yellowish needles, very soluble in water.
7.
AMMONIUM THIOCYANATE. SATURATED SOLUTION. MICROCHEMICAL TEST.
a)
(Ephedrine in ten per cent solution.) Elongated prisms. (Fig. 10.)
b )
c) (Five to ten per cent.) Rhombic hemihedral plates. (Fig. 12.)
d )
e )
(Saturated solution
of
pseudoephedrine hydrochloride.)
It
sets
to a
glassy paste
not showing discrete crystals.
(Fig. 11.
(Two and a half to five per cent.)
Two
and half to five per cent. )
Leaflets crystallize out
on
standing from th e oily
Oily droplets, which do not crystallize, separate
droplets which first separate out.
out.
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1244
JOURNAL
OF THE Vol.
XXII, No.
12
c f
(One to two and a half per cent.)
Prismatic hemihedral plates. All of the above
were readily soluble on th e addition of water.
8. PHOSPHOMOLYBDIC
ACID. TEN
PER
CENT.
All of the compounds with this reagent yielded
a
pale yellow precipitate, which became
blue on standing for a definite length
of
time varying, with t he compound tested:
(f) Methyl-ephedrine-methyl-iqdide
d ) Butyl-ephedrine hydrochloride
e)
Benzyl-ephedrine hydrochloride
a )
Ephedrine hydrochloride (2)
b ) Pseudoephedrine hydrochloride
(c)
Methylephedrine hydrochloride
In
1
to 2 days
In 2 to
3
days
In 3 to 4days
In 4 o 6 days
In 6 to 20 days
In 0 to
20
days.
9.
POTASSIO-MERCURIC
IODIDE. MAYER’S REAGENT.
The
compounds all yielded a whitish precipitate, the solubility in water or dilute acids
varying with the compound used.
a) and
b )
Readily soluble.
(c)
Soluble.
d ) and e )
f) Almost insoluble.
Not very soluble.
10. POTASSIUM TRI-IODIDE. WAGNER’S REAGENT.
A strong solution of iodine five per cent and potassium iodide five per cent gave brown
precipitates with all the compounds. The reagent diluted 0.2 per cent, gave no permanent pre-
cipitate with ephedrine in one per cent solution and only a cloudy effect with pseudoephedrine
one per cent. Butyl and benzyl-ephedrine in dilute solution
of
0.1
per cent gave heavy precipi-
tates.
11. POTASSIUM BISMUTH IODIDE. KRANT’S OR
THRESH’S
REAGENT.
A
reddish precipitate insoluble in water is produced by all the compounds but on the
addition of acetic acid
a) .
b ) and c) were readily soluble,
(d)
and e ) were difficultly soluble
and (f) was almost insoluble. (Tsiang and Brown
(7)
used this test with ephedrine
1
in 1000
solution.)
12.
MERCURIC CHLORIDE. FIV E PER CENT,
No
precipitate was obtained from a ) , b ) or c) in five per cent solutions,
d) , e )
and
f)
yielded white precipitates soluble in excess of the reagent, or on the addition of water and weak
acids.
13. SODIUM NITROPRUSSIDE.
FIVE
PER CENT.
Only butyl-ephedrine and benzyl-ephedrine in five per cent solution formed flesh-white
precipitates, soluble in excess of water.
14.
BISMUTH NITRATE.
FIVE PER CENT, SLIGHTLY ACIDIFIED WITH NITRIC ACID.
They all yield white precip itates soluble in excess
of
nitric acid.
This test is more sensitive
than some, especially with the quaternary halides c f , each of which give
a
characteristic result
described in another report
4).
One of these quaternary compounds might be used t o estimate
bismuth.
15. AMMONIUM MOLYBDATE. FI VE PER CENT.
All the compounds form white precipi tates soluble in excess
of
the reagent or on the addi-
tion of water, the solubilities decreasing in t he order ci ted, as was th e case in o ther te sts.
16.
PHOSPHOTUNGSTIC
ACID. TEN PER CENT.
White curdy precipitates of nonspecific character were produced by all the compounds.
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Dec.
1933
AMERICAN
PHARMACEUTICAL ASSOCIATION 1245
17. ZINC--OR-IODIDE.
STEPHENSON S REAGENT.
There was obtained in all cases a brownish white precipi tate insoluble on the addition of
water, but soluble in dilute acetic acid.
18.
REAGENTS
WITH
NO VISIBLE REACTION.
Tannic acid, barium nitrate, cobalt chloride, glucose, glycerine, manganese chloride,
nickel chloride, phthalic acid, potassium ferri and ferrocyanides, sodium benzoate or nitrite.
The reactions with potassium permanganate and chromic acid were
so
unstable that they seem
worthless as test reagents for this class
of
compound.
NOTE.
Many of the above tests confirm earlier reports upon the various reactions of
ephedrine, but this is the only comprehensive statement dealing with solutions of
known strengths.
LITERATURE CITED.
K. K. Chen,
JOUR.
A.
PH.
A.,
14 1925), 189-194.
K.
K. Chen and
C. H.
Kao,
Ibid., 15 1926), 625-639.
C.
T. Feng, Chinese J. Physiol. ,
1 1927), 397-406.
C T. Feng, JOUR.
A.
PH.A. ,
21 1932),
8-15.
C. T.
Feng and B. E. Read, Chinese
J.
hysiol. ,
1928), 87-96.
B.
E.
Read and
C . T.
Feng, Ibid. ,
1 1927), 297-304.
K. Tsiang and E. D. Brown, JOUR. A. PH.A.,
16 1927), 294-296.
1)
2)
3)
4)
5)
(6)
7)
A NOTE
ON THE
WATER CONTENT
OF
MAGNESIUM OXIDE.*,
BY
JACOB
E. SCHMIDT AND JOHN C.
KRANTZ,
JR.
INTRODUCTION.
The Pharmacopoeia recognizes dual standards for magnesium oxide and heavy
magnesium oxide. The rubric requires 96 per cent purity after ignition and per-
mits 10 per cent water to be present in the compounds in general use. In the prepa-
ration of the monographs for these compounds for the forthcoming edition
of
the
Pharmacopoeia, the authors had occasion to examine several commercial samples of
each variety
of
magnesium oxide. The percentage of water found in the specimens
showed great variation. In many instances the water content
of
the light variety
exceeded the Pharmacopoeia1 limit. The highest quantity of water found was 22
per cent.
On
account of these findings, the authors investigated the problem and recorded
their observations in this communication.
TABLE.-PERCENTAGE
F WATERN COMMERCIALAMPLESF MAGNESIUMXIDE.
Light.
Heavy. Light.
No. Per
Cent
Water. Per Cent Water.
No. Per
Cent Water.
1 22 .0 7 . 8
8
11.5
2 20.3 7 . 8 9 18.0
3
20.3 7 .8 10 21.9
4
19.2 3 . 4 11 19.3
5
19.4 6 .5 12 22.5
6
14.0 13 14. 5
7 17.9
Mean
18.5
per cent
Scientific Section, A. PH.
A.,
Madison meeting,
1933.
The expense of this investigation was defrayed in part
by
a grant from the Research Fund
of
the AMERICANHARMACEUTICALSSOCIATION.